SUMMARY The standard of care for genetic testing of hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome is based on guidelines from the NCCN. The paradigm was developed based on the principle that genetic testing was expensive and that the incidence of these syndromes was low. Over the past twenty years the price of testing has fallen dramatically and it is now recognized that both HBOC and Lynch syndrome are relatively common (joint incidence of about 1 in 200). Many individuals in the population are affected by HBOC or Lynch but come from small families with few female relatives. Given the decreases in family size that have occurred over the past 50 years this is becoming a common situation. It is estimated that only 20% of those affected by HBOC are aware of their condition. Overall, there is a significant unmet need for those with HBOC and Lynch syndrome to be identified so they can have the opportunity for appropriate medical care. What we need are approaches that can rapidly, accurately, and inexpensively identify those with inherited cancer syndromes. The costs of sequencing have fallen dramatically and members of our team have QIAseq based targeted resequencing platforms for germline studies that dramatically lower the cost of panel based sequencing while allowing easy, rapid multiplexing. The costs of testing will be near $90 per sample. We have taken the task of developing a strategy that can be applied to detect HBOC and Lynch syndromes in broader populations. We will study the effectiveness of population scale testing of these two syndromes by enrolling 27,500 individuals, who are (a) eligible for inherited cancer syndrome testing (2,500) (b) have had cancer but are not covered by current screening guidelines to receive a low cost genetic screen (7,500) or (c) healthy (17,500). Those individuals identified to have Lynch or HBOC will be followed for outcomes and compared to a matched cohort identified following standard screening guidelines. Additionally, relatives of those identified will be enrolled in cascade screening. We will determine if testing either cancer patients or the general population represents a sustainable strategy for population screening based on QALY measurements.